HR+/HER2+ Breast Cancer PFS Improved With Abemaciclib

Patients with advanced hormone receptor&ndash;positive, HER2-positive breast cancer had improved progression-free survival when receiving the CDK4/6 inhibitor abemaciclib and endocrine therapy with trastuzumab compared with trastuzumab and chemotherapy, according to findings from the randomized phase II monarcHER trial.<sup>1</sup>

Sara Tolaney, MD

Patients with advanced hormone receptor (HR)—positive, HER2-positive breast cancer had improved progression-free survival (PFS) when receiving the CDK4/6 inhibitor abemaciclib (Verzenio) and endocrine therapy with trastuzumab (Herceptin) compared with trastuzumab and chemotherapy, according to findings from the randomized phase II monarcHER trial.1

Patients who received abemaciclib and fulvestrant (Faslodex) in addition to trastuzumab had a median PFS of 8.32 months versus 5.69 months for patients treated with the current standard of trastuzumab and chemotherapy. More than twice as many patients had objective responses with the investigational regimen as with trastuzumab and chemotherapy.

A third randomized cohort received abemaciclib and trastuzumab without fulvestrant, which led to outcomes similar to the trastuzumab-chemotherapy control group, as reported at the 2019 ESMO Congress.

“This is the first randomized study of a CDK4/6 inhibitor and endocrine therapy with trastuzumab, compared to chemotherapy and trastuzumab, in patients with advanced hormone receptor [HR]-positive, HER2-positive breast cancer,” said Sara Tolaney, MD, Dana-Farber Cancer Institute in Boston, Massachusetts. “The study demonstrated that in a heavily pretreated population, the combination of abemaciclib with fulvestrant and trastuzumab led to a statistically significant improvement in both progression-free survival and the objective response rate, compared to chemotherapy and trastuzumab.

“There were no new safety signals identified, and generally, the regimen was well tolerated. These data suggest that abemaciclib with endocrine therapy has activity not just in patients with HR-positive, HER2-negative, but also in patients with HR-positive, HER2-positive disease.”

The rationale for clinical evaluation of abemaciclib-fulvestrant in HR-positive, HER2-positive breast cancer included in vivo evidence that CDK4/6 inhibition by abemaciclib enhanced activity of HER2-directed agents. Additionally, combined inhibition of CDK4/6 and HER2 had synergistic activity in a preclinical model of resistance to HER2-directed therapies.2

A phase I trial provided additional evidence that abemaciclib has clinical activity in HR-positive, HER2-positive breast cancer, reflected in an objective response rate of 36% and median PFS of 7.2 months.3Several studies showed that the addition of HER2-directed therapy to endocrine therapy improved PFS in patients with HR-positive, HER2-positive breast advanced breast cancer, said Tolaney, associate director, Susan F. Smith Center for Women's Cancers and assistant professor of medicine, Harvard Medical School.

The evidence led to the development of an international, multicenter phase II randomized trial of abemaciclib and fulvestrant in pretreated HR-positive, HER2-positive advanced breast cancer. Eligible patients had received at least 2 prior HER2-directed therapies for advanced breast cancer, including required exposure to T-DM1 and a taxane. Patients previously treated with a CDK4/6 inhibitor with fulvestrant were not eligible.

Investigators randomized 237 patients to 3 treatment regimens: abemaciclib with trastuzumab and fulvestrant; abemaciclib plus trastuzumab; and trastuzumab plus investigator’s choice of chemotherapy. The primary endpoint was PFS for the comparison of each of the abemaciclib arms versus the trastuzumab-chemotherapy control arm.

Tolaney said baseline characteristics were well balanced among the 3 groups, including geographic distribution (Asia/Pacific, Europe, North America, and South America), metastatic sites, prior systemic therapies, prior endocrine therapies, and prior HER2-directed therapies.

The primary analysis showed that treatment with the abemaciclib-fulvestrant-trastuzumab regimen resulted in a 37% reduction in the hazard ratio for disease progression or death versus the trastuzumab-chemotherapy arm (P= .0506). The abemaciclib-trastuzumab regimen led to a median PFS of 5.65 months, which did not differ from the median PFS of the control group.

Abemaciclib and fulvestrant with trastuzumab led to an objective response rate of 32.9% versus 13.9% in each other 2 groups (P = .0042 versus control group). Similar results emerged from an analysis limited to patients with measurable disease (36% versus 16% for the other 2 groups, P= .0111).

An exploratory analysis of overall survival (OS) showed an early trend in favor of both abemaciclib groups. The median OS was 24.33 months with fulvestrant, 24.07 months without fulvestrant, and 21.50 months with trastuzumab and chemotherapy. Tolaney said the final OS analysis is not expected to occur until 2021.

Overall, grade ≥3 treatment-emergent adverse events (TEAEs) occurred more often with the abemaciclib-fulvestrant-trastuzumab regimen (56.4% vs 37.7% vs. 33.3%). Serious adverse events also occurred more often with abemaciclib-fulvestrant (10.3% vs 5.2% vs. 6.9%). Rates of fatal adverse events and discontinuation because of adverse events were similar across the 3 groups.

The most common grade ≥3 TEAEs with abemaciclib-fulvestrant were neutropenia (26.9%), leukopenia (10.3%), thrombocytopenia (10.3%), diarrhea (9.0%), anemia (9.0%), hypokalemia (5.1%), and fatigue (3.8%).

During the discussion that followed her presentation, Tolaney was asked to speculate about whether patients treated with the triplet regimen might have done just as well with fulvestrant and trastuzumab.

The superior PFS and response rate with the triplet combination “were more likely due to synergistic activity of the 3 drugs, and I think that’s probably true for a couple of reasons,” said Tolaney. “This was a heavily pretreated population with a median of 4 prior lines of systemic therapy in the metastatic setting, and 54% of the patients had already received endocrine therapy for advanced disease. I think it’s unlikely you would have seen benefit from fulvestrant and trastuzumab.

“I also think the activity we’re seeing with abemaciclib trastuzumab is really on par with chemotherapy and trastuzumab. I think the effect we’re seeing is more likely due to the additive effects and synergistic activity with the addition of fulvestrant.”


  1. Tolaney S, Wardley A, Zambelli S, et al. MonarcHER: A randomized phase II study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of care chemotherapy in women with HR+, HER2+ advanced breast cancer. Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. LBA23.
  2. Goel S, Wang Q, Watt AC, et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors.Cancer Cell. 2016;29(3):255-269. doi: 10.1016/j.ccell.2016.02.006.
  3. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors.Cancer Discov. 2016;6(7):740-753. doi: 10.1158/2159-8290.CD-16-0095.